Persistent immune activation is the hallmark of lentiviral infection in AIDS-susceptible species. p38 MAPK, activated in HIV and SIV infection, is key to induction of Interferon-stimulated genes (ISG) and inflammatory cytokines and is associated with some of the pathology produced by HIV and SIV infection in AIDS-susceptible primates. As small molecule p38 MAPK inhibitors are currently tested in human trials for other inflammatory diseases, we evaluated the effects of treating SIV-infected macaques with a p38 inhibitor, PH-797804, in conjunction with ART.
Rhesus macaques were infected with SIVmac251 and divided in 6 groups: Group 1, had no treatment, Group 2, p38 inhibitor alone, Groups 3 and 5 initiated ART at week 6 or 1 after infection, Group 4 and 6 initiated ART + PH797804 at week 6 or 1 after infection. ART efficacy was evaluated by measuring viral loads and reservoirs. As primary endpoints for PH-797804 efficacy, we evaluated protein levels of selected ISG and differences in expression of surface and intracellular molecules linked to immune activation and inflammatory cytokines plasma levels. As secondary endpoints, we evaluated effects of treatment on viral loads, reservoirs, and immune system preservation.
ART treatment reduces viremia to very low or undetectable levels. PH797804 had no side effects, did not further reduced the viremia, and did not affect immune responses to SIV. Administered alone, it had no significant effect on immune activation. When combined with ART, numerous immune activation markers were significantly reduced compared to ART alone treatment. CD38/HLA-DR and Ki-67 percentages in blood, lymph node and rectal CD4+ and CD8+ T cells and plasma levels of IFN-, IL-6, IL-8, and IP-10 were all significantly reduced. IRF7, pSTAT1 and IP-10 protein accumulation was also reduced. Significant preservation of CD4+/IL22+, CD4+ CM T-cells and improved ratio of Th17+/ Treg+ /CD4+ T cell was observed. After ART interruption, viremia rebounded in a similar fashion in the groups that received ART, with or without the inhibitor.
The p38 MAPK inhibitor used here, already in clinical trials for other inflammatory diseases, significantly reduced immune activation during ART and further reduced SIV-mediated immune system deterioration. However, suppression was not complete and was approximately 65% of that of untreated animals. Residual SIV replication in tissues during ART is under investigation.